ITMI20120586A1 - CO-CRYSTALS OF 3-IODIOPROPINYL BUTYCARBAMMATE - Google Patents

Description

â € œCO-CRYSTALS OF 3-IODOPROPINYL BUTYL CARBAMATEâ €

Field of the invention

The present invention relates to biocidal agents for the protection of industrial products from microbial, bacterial, fungal or algae infestations. In particular, the present invention refers to co-crystals containing 3-iodopropinyl butylcarbamate (IPBC) and to compositions containing said co-crystals, which show improved physical, chemical and processing properties with respect to the use of IPBC.

Description of the state of the art

3-iodopropinyl butylcarbamate (IPBC) is a biocide used as a preservative, fungicide and algaecide in industrial formulations such as paints, coatings, in metalworking and in the protection and preservation of wood. It is also added to polymer formulations to prevent the growth of fungi and bacteria in products made from polymers. It is also present in personal care and cosmetic products to prevent the growth of bacteria and fungi.

In some of its applications, IPBC can be directly added to the formulation of interest at room temperature. However, the compound is difficult to use in industrial products and processes. It has an extremely low water solubility (156 ppm at 20 ° C) and tends to be inhomogeneous and sticky which makes it unsuitable for automatic fabrication devices. The product melts at a temperature of 67 ° C, above which it degrades rapidly. It is therefore considered unusable in compositions that must be used above said temperature.

The product can be prepared in high yield and purity as described in US 6,999,208.

The crystalline and molecular structure of IPBC was described by E.V. Avtomonov et al, Zeitschrifit fuer Naturforschung, B: Chemical Sciences, 52 (2), 256-258, 1997.

Co-crystals between IPBC and a second component are not known.

The definition of co-crystal has long been debated in crystallography. The simplest definition is that of a crystalline structure consisting of two or more components in a precise stoichiometric ratio, where each component can be an atom, an ion or a molecule (G.P. Stahly et al., A survey of co-crystals reported prior to 2000, Crystal Growth & Design, 9 (10), 4212-4229, 2009). However, this definition includes many types of compounds, such as hydrates, solvates and clathrates and for this reason the definition is sometimes extended by specifying that the components of the co-crystals are solid in their pure forms under ambient conditions (J. H. ter Horst et al, Discovering new co-crystals, Crystal Growth & Design. 9 (3), 1531-1537, 2009). Another definition in the literature is that co-crystals consist of two or more components that form a single crystalline structure with unique properties (G.P. Stahly, Diversity in Single- and Multiple-Component Crystals. Prevalence of Polymorphs and Cocrystals, Crystal Growth & Design 7 (6), 1007-1026, 2007).

Co-crystals are ordered structures and the components interact through non-covalent interactions, such as hydrogen bonds, ionic interactions, van der Waals interactions and Ï € interactions. The properties of co-crystals, such as melting point, solubility, chemical stability and mechanical properties, differ from those of the individual components.

The formation of co-crystals in which one of the components is a substance with biological activity represents an approach increasingly pursued in the pharmaceutical field as it allows to optimize the chemical-physical properties of the active ingredient of interest. See for example: M. J. Zaworokto et al, The role of cocrystals in pharmaceutical science, Drug Discovery Today, 13, 440, 2008; O. Almarsson et al, Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical cocrystals represent a new path to improved medicines? Chem .. Comm., 1889, 2004; P. Vishweshwar et al, Pharmaceutical cocrystals. J.Pharm. Sciences, 95, 499, 2006; A. V. Trask, An overview of pharmaceutical cocrystals as intellectual property. Mol. Pharma.

4, 30, 2007; W. Jones et al., Pharmaceutical cocrystals: an emerging approach to physical property enhancement. MRS Bull. 31, 875, 2006.

Examples of co-crystallization approaches to generate new supramolecular materials are reported in US2011152266 (A1), GB2476202 (A), CA2738866 (A1), WO2011035456 (A1), KR20100091127 (A), WO2010011926 (A2), WO2010128977 (A1), MX2008015937 (A), KR20090015912 (A), WO2009116055 (A1), US2009247749 (A1), WO2008108639 (A1), US2008280858 (A1), WO2008021559 (A2), WO2007067727 (A2), US2006149521 (A1), CN1757780 ( WO2005089375 (A2). In all cases, co-crystals are formed by non-covalent interactions involving hydrogen bonds, Ï € -Ï € (stacking) or €-Ï € interactions.

Methods for generating new molecular entities involving IPBC are described in US20040143011A1 and in US7851516B2. However, these documents do not suggest the formation of co-crystals involving the iodoacetylenyl group and the halogen-bonded interaction such as those object of the present application.

Definitions

For the purposes of the present application a co-crystal is defined as a crystal which contains in the unit crystalline cell at least one molecule of IPBC and at least one molecule of a second compound, called co-crystallization agent, which can be liquid or solid at room temperature. However, the term co-crystallization agent does not include water or solvents.

For the purposes of this application, the term â € œhalogen bondâ € (XB) indicates a non-covalent interaction involving the iodine atom of IPBC, which acts as an electron density acceptor. This type of bond is indicated in the present question with the graphical representation D --- I, in which I is the iodine atom (Lewis acid, electron acceptor, donor-XB) and D is a species electron donor (Lewis base, XB acceptor). For a discussion of halogen bonding see P. Metrangolo, F. Meyer, T. Pilati, G. Resnati, G. Terraneo, Halogen Bonding in Supramolecular Chemistry, Angewandte Chemie International Edition, Volume 47 (33), 6114-6127, 2008.

Description of the invention

Object of the present invention are co-crystals of the compound 3iodopropinyl butylcarbamate with a co-crystallization agent, in which said agent is in the liquid or solid state at room temperature and is bound to IPBC through at least one halogen bond. The co-crystals object of the invention have advantageous chemical-physical properties compared to IPBC, such as better water solubility, greater thermal stability, better flowability of the powders and better compressibility for the formation of tablets.

The co-crystals of the invention are obtained by solid state or solution synthesis. Their formation can be achieved through a supramolecular approach of assembly between IPBC with selected chemical species, called co-crystallization agents, which are able to establish non-covalent interactions involving the iodine atom (halogen bond, XB ) present on the molecular structure of IPBC. The co-crystallization agents used in the present invention are organic bases, in particular aliphatic amines or aromatic heterocyclic derivatives containing at least one basic nitrogen atom, halides, phosphates, carboxylates.

A further object of the invention is a composition containing a co-crystal as defined above and additives.

A further object of the invention is the use of a co-crystal as defined above, or of a composition as defined above, as a biocide, in particular as a preservative, antibacterial, fungicide or algaecide.

A further object of the invention are industrial products containing a co-crystal as defined above.

Finally, a further object of the invention is a process for the preparation of a co-crystal as defined above, comprising: a) putting IPBC in contact with a co-crystallization agent capable of forming at least a halogen bond with said IPBC, in conditions of crystallization such as to form a solid phase in which the IPBC and said agent are linked together by at least one halogen bond; and, b) optional isolation of the co-crystals formed in step a).

Detailed description of the invention

In one embodiment of the invention, the co-crystallization agent is selected from among the aromatic heterocycles containing at least one nitrogen atom of a basic nature and is preferably selected from derivatives of pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, thiazole , isothiazole, oxazole, isoxazole and their benzocondensated derivatives, for example quinoline and isoquinoline. Preferably the pyridine derivatives useful as co-crystallization agents have the general formula (I)

<N> L N

(THE)

where L is chosen from - (CH2) n-, where n is 0 or an integer from 1 to 6, and -C (O) -NH- (CH2) m-NH-C (O) -, in which m is an integer from 2 to 6, and in which one or both of the pyridine rings can be benzocondensed.

In a preferred embodiment, the compounds of formula (I) are selected from 4,4â € ™ -bipyridyl, 4- [2- (4-pyridinyl) ethyl] pyridine and N, Nâ € ™ -bis (4-pyridylcarbonyl) -1 , 6-hexanediamine.

In another embodiment of the invention the co-crystallization agent is an aliphatic amine with formula R <1> R <2> R <3> N in which R <1>, R <2 > and R <3> are independently selected from the group of hydrogen, C1-C6alkyl, C3-C7cycloalkyl; or R <1> is as defined above and R <2> and R <3>, taken together with the nitrogen atom to which they are bonded, form a 4-7-membered heterocyclic nitrogen ring optionally containing an oxygen atom or sulfur or a further nitrogen atom, said further nitrogen atom being replaced by a group R <1> as defined above.

Examples of aliphatic amines useful for the purposes of the present invention are triethylamine, diisopropylethylamine, tributylamine, N-methylpiperidine, N-methylmorpholine, N, Nâ € ™ -dimethylpiperazine.

In another embodiment of the invention the co-crystallization agent is an organic or inorganic halide.

When an organic halide is used, it is preferably a tetraalkylammonium halide of formula R4N <+> X <-> in which each R can be independently a C1-C6 alkyl and X <-> is a halide.

In a preferred embodiment the organic halide is tetrabutylammonium iodide.

In another embodiment of the invention the co-crystallization agent is an inorganic halide and is preferably the halide of an alkaline, alkaline earth or transition metal chosen between iron and zinc, or a tin halide. Examples of inorganic halides usable as co-crystallization agents according to the present invention are: iodides such as cuprous iodide and potassium iodide; chlorides such as ammonium chloride, magnesium chloride, potassium chloride, stannous chloride, calcium chloride, ferric chloride, sodium chloride, zinc (II) chloride.

In a preferred embodiment, the inorganic halide is calcium chloride.

In another embodiment of the invention the co-crystallization agent is an inorganic phosphate, for example monobasic ammonium phosphate, dibasic ammonium phosphate, dibasic magnesium phosphate, tribasic magnesium phosphate, monobasic calcium phosphate , dibasic calcium phosphate, tribasic calcium phosphate, calcium pyrophosphate, ferric phosphate, ferric pyrophosphate, monobasic potassium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, potassium pyrophosphate, sodium aluminum phosphate, monobasic sodium phosphate , dibasic sodium phosphate, tribasic sodium phosphate, sodium pyrophosphate.

In another embodiment of the invention the co-crystallization agent is a carboxylate of an alkali metal, alkaline earth or a transition metal. Examples of carboxylates useful for the purposes of the present invention are acetates, for example calcium acetate, sodium acetate, zinc acetate; citrates, for example ammonium citrate, calcium citrate, iron (III) citrate, iron (III) and ammonium citrate, sodium citrate and potassium citrate; benzoates, for example sodium benzoate.

In the co-crystals of the invention, IPBC and the co-crystallization agent are present in a molar ratio ranging from 2: 1 to 4: 1.

Preferred co-crystals of the invention are:

- co-crystal containing 3-iodopropinyl butylcarbamate and 4- [2- (4-pyridinyl) ethyl] pyridine in a 2: 1 molar ratio;

- co-crystal containing 3-iodopropinyl butylcarbamate and 4,4â € ™ -bipyridine in a molar ratio of 2: 1;

- co-crystal containing 3-iodopropinyl butylcarbamate and tetrabutylammonium iodide in a molar ratio of 3: 1;

- co-crystal containing 3-iodopropinyl butylcarbamate and calcium chloride in a 4: 1 molar ratio;

- co-crystal containing 3-iodopropinyl butylcarbamate and N, Nâ € ™ -bis (4-pyridylcarbonyl) -1,6-hexanediamine in a 2: 1 molar ratio.

Further preferred co-crystals of the invention are:

- co-crystal containing 3-iodopropinyl butylcarbamate and 4- [2- (4-pyridinyl) ethyl] pyridine in a 2: 1 molar ratio, having characteristic X-ray diffraction peaks of powders (XRPD) at 2Î ̧ angles of 5.12, 5.68, 11.44, 16.95, 22.22, 22.66, 24.97 and 27.88 ± 0.05 °, and unit cell size [a = 30,666 (3) b = 4.9869 (4) c = 21.068 (2)] and [Î ± = 90.00 β = 92.115 (6) γ = 90.00];

- co-crystal containing 3-iodopropinyl butylcarbamate and 4,4â € ™ -bipyridine in a 2: 1 molar ratio, having characteristic X-ray diffraction peaks of powders (XRPD) at 2Î ̧ angles of 6.23 and 21 , 93 ± 0.05 °, and unit cell dimensions [a = 28.683 (2) b = 4.9270 (4) c = 21.429 (2)] and [Î ± = 90.00 β = 99.92 (2) γ = 90.00];

- co-crystal containing 3-iodopropinyl butylcarbamate and tetrabutylammonium iodide in a 3: 1 molar ratio, having characteristic powder X-ray diffraction peaks (XRPD) at 2Î ̧ angles of 9.28, 14.48, 16, 32, 17.73, 20.25, 20.69, 21.10, 21.33, 22.26, 22.90, 23.60, 23.97, 24.30, 25.01, 26.13, 26.51, 27.90 and 28.40 ± 0.1 ° and unit cell dimensions [a = 10.7688 (9) b = 20.204 (2) c = 23.735 (2)] and [Î ± = 90.00 β = 94.778 (2) γ = 90.00];

- co-crystal containing 3-iodopropinyl butylcarbamate and calcium chloride in a 4: 1 molar ratio, having characteristic powder X-ray diffraction peaks (XRPD) at 2Î ̧ angles of 9.67 and 22.28 ± 0 05 °;

- co-crystal containing 3-iodopropinyl butylcarbamate and N, Nâ € ™ -bis (4-pyridylcarbonyl) -1,6-hexanediamine in a molar ratio 2: 1, having characteristic X-ray diffraction peaks of powders (XRPD) to values of angles 2Î ̧ of 11.83 and 22.78 ± 0.05 °, and having unit cell dimensions [a = 29.4501 (18) b = 5.1100 (3) c = 27.9417 (17)] and [Î ± = 90.00 β = 118.566 (3) γ = 90.00].

By characteristic peaks in the XPRD spectrum of powders we mean peaks with relative intensity greater than 40% with respect to the peak of greater intensity, set equal to 100.

The crystallization methods used for the preparation of the co-crystals of the invention include the slow and fast evaporation of solutions containing IPBC and the co-crystallization agent in the desired stoichiometric ratios, in which the formation of the co- crystal occurs in solution by slow and fast evaporation of the solvent; fast precipitation from nearly saturated solvent solutions containing IPBC and the co-crystallization agent; dry grinding or in the presence of drops of solvent of a mixture of IPBC and the co-crystallization agent; the fusion of the mixture of IPBC and the co-crystallization agent; solid phase mechano-chemical synthesis in a ball mill; or a combination of said methods. The choice of one or more of these methods is made considering the physical state (solid or liquid) of IPBC and / or of the co-crystallization agent at the temperature at which the formation of the co-crystal is carried out.

In one embodiment of the invention the synthesis of the co-crystals occurs in solution.

In the event that both IPBC and the co-crystallization agent are both in the solid state, each substance, in the exact molar ratios, is dissolved separately in a suitable solvent, for example methanol, ethanol, chloroform, dichloromethane, acetonitrile and acetate of ethyl. The two solutions are then mixed together and the resulting mixture is allowed to evaporate. Evaporation is done slowly if it is required to obtain a single crystal, or quickly, for example with the help of a vacuum evaporation system, if you want to obtain the co-crystal in the form of dust.

In the case, on the other hand, in which the co-crystallization agent is liquid, an almost saturated solution of IPBC is prepared in a suitable solvent, for example methanol, ethanol, chloroform, dichloromethane, acetonitrile and ethyl acetate. The liquid co-crystallization agent is then added to this solution in an exact molar ratio. The resulting mixture is allowed to evaporate. Evaporation is done slowly if it is required to obtain a single crystal, or quickly, for example with the help of a vacuum evaporation system, if you want to obtain the co-crystal in the form of powder.

In another embodiment of the invention, the synthesis of co-crystals occurs in the solid state. IPBC and the co-crystallization agent, weighed in the exact molar ratio desired for the co-crystal, are mixed together and placed in a metal container of various sizes. One or more metal balls of various sizes are inserted inside the container. The container is placed in a ball mill and is made to vibrate with a frequency of 10-30 Hz for a variable time between 5 and 30 minutes, depending on the size of the container. The product recovered from the container is the co-crystal, which does not require further purification.

The co-crystals of the invention containing IPBC are suitable for the protection of industrial materials, such as adhesives, glues, paper, cardboard, leather, wood and wood-based materials, coating materials, paints, plastic materials, refrigerants industrial, industrial lubricants, metalworking fluids, personal care products such as wet wipes, toilet paper, cosmetic products, and other materials that can be infested or decomposed by microorganisms. Examples of microorganisms that can cause the degradation or alteration of industrial materials and against which the co-crystals of the invention can be advantageously used are bacteria, fungi, in particular fungi and molds that attack wood, yeasts, algae and mucous organisms such as â € œslimeâ €. Specific examples are microorganisms of the genus Alternaria, for example Alternaria tenuis, Aspergillus, for example Aspergillus niger, Chaetomium, for example Chaetomium globosum, Coniophora, for example Coniophora puetana, Lentinus, for example Lentinus tigrinus, Penicillium, for example Penicillium glaucum, Polyporus, eg Polyporus versicolor, Aureobasidium, eg Aureobasidium pullulans, Sclerophoma, eg Sclerophoma pityophila, Trichoderma, eg Trichoderma viride, Escherichia, eg Escherichia coli, Pseudomonas, eg Pseudomonas aerugoccus, eg Staphylococcus.

According to their chemical and physical properties, the co-crystals of the invention can be incorporated in formulations such as solutions, emulsions, suspensions, powders, foams, pastes, granules, tablets, aerosols or microencapsulated in polymeric substances. The formulations of the invention can be prepared using conventional methods. For example, the formulations can be prepared by mixing the co-crystals with diluents, for example liquid solvents or liquefied gases under pressure, and / or with solid diluents, if necessary also using surfactants, for example emulsifying agents and / or dispersants and / or foaming agents. If the diluent used is water, it is also possible to use organic solvents as co-solvents. Usable solvents are aromatic solvents such as for example toluene, xylene; aliphatic or aromatic chlorinated hydrocarbons such as dichloromethane and chlorobenzene; aliphatic hydrocarbons, such as for example cyclohexane; alcohols such as for example butanol, ethylene glycol and their ethers and esters; ketones such as for example acetone and ethyl methyl ketone, or cyclohexanone; very polar solvents such as water, dimethyl sulfoxide and dimethylformamide. Examples of liquefied gases under pressure are liquids that are gaseous at ambient pressure and temperature such as halogenated hydrocarbons, butane, propane, nitrogen and carbon dioxide.

Suitable solid diluents are natural or synthetic pulverized minerals such as for example kaolins, clays, talc, gypsum, quartz, diatomaceous earth and silica, alumina and silicate powders.

Suitable emulsifying and / or foaming agents are, for example, non-ionic or anionic emulsifying agents such as polyoxyethylene esters with fatty acids, ethers between polyoxyethylene and fatty alcohols, alkyl- or aryl-sulfonates, alkylsulfates. Example of a suitable dispersing agent is methylcellulose.

The formulations generally contain between 0.1% and 95% by weight of the co-crystals, preferably between 2% and 75% by weight.

A further object of the present invention are therefore compositions with biocidal activity containing an IPBC co-crystal of the invention and at least one solvent or diluent. The compositions of the invention can also contain additives which help the process of obtaining the composition and, if necessary, other biocidal agents such as agents with antimicrobial activity, fungicides, bactericides, herbicides, insecticides, algaecides. In this case the co-crystals of the invention and of the other biocidal agents can be present in solution, suspension or emulsion. The solvents or diluents can be water or conventional organic solvents. The compositions containing as active components a co-crystal of the invention and another biocidal agent can show a broader spectrum of action than the single active components and / or a synergistic effect. Examples of other biocidal agents that may be present in the compositions of the invention include azaconazole, bromuconazole, cyproconazole, dichlorobutrazole, diniconazole, diuron, hexaconazole, metaconazole, penconazole, propiconazole, tebuconazole, diclofluanide, cyclofluorphetol, tolofluanide, tolorfluorphetide, benzo [b] thiophenecarboxamide S, S-dioxide, phenpiclonyl, 4- (2,2-difluoro-1,3-benzodioxol-4-yl) -1H-pyrrole-3-carbonitrile, butenaphine, imazalyl, N-methyl-isothiazolin -3-one, 5-chloro-N-methylisothiazolin-3-one, N-octylisothiazolin-3-one, dichloro-N-octylisothiazolinone, mercaptobenzothiazole, thiocyanate-methylthiobenzothiazole, thiabendazole, benzoisothiazolinone-amoxypanine-hydroxy-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-meth benzyl hemiformal, N-methylol-chloroacetamide, N- (2-hydroxypropyl) aminomethanol, glutaraldehyde, omadine, Zn-omadine, dimethyl dicarbonate, 2-bromo-2-nitro-1,3-propanediol, betoxazine, o-phtaldialdehyde, 2 , 2-dibromo-3-cyanopropionamide, 1,2-dibromo-2,4-diciano-butane, 1,3-bis (hydro ssimethyl) -5,5-dimethylimidazolidin-2,4-dione (DMDMH), tetramethylolacetylenedurea (TMAD), hemiformal ethylene glycol, p-hydroxybenzoic acid and ac. p-hydroxybenzoate (parabens), e.g. ethyl p-hydroxybenzoate (E214), ethyl p-hydroxybenzoate sodium salt (E215), propyl p-hydroxybenzoate (E216), propyl p-hydroxybenzoate sodium salt (E217), methyl-p-hydroxybenzoate (E218) and methyl-hydroxybenzoate sodium salt (E219), carbendazim, chlorophene, 3-methyl-4-chlorophenol, o-phenylphenol.

The weight ratio between the co-crystals of the invention and the other biocidal agents can vary over a wide range. Preferably said ratio ranges from 50: 1 to 1:50.

The compositions with antimicrobial activity of the invention contain the co-crystals of the invention or a mixture of the co-crystals of the invention and another biocidal agent in a concentration between 0.1% and 95% by weight, preferably between 0.1% and 60% by weight.

The concentrations in which the co-crystals of the invention or their combination with another biocidal agent are used depend on the nature and incidence of the microorganisms that need to be controlled and also on the composition of the material to be protected. The optimal amount for use can be determined by a series of assays. In general, for most applications the concentrations are between 0.001% and 5% by weight, preferably between 0.05% and 2% by weight, depending on the material to be protected.

The compositions containing the co-crystals of the invention produce an improvement of the physical and chemical properties (for example greater solubility in water and a greater thermal stability) and of the processing properties (for example a better flowability of the powders and a better compressibility for tablet formation) with respect to compositions containing IPBC.

A further object of the invention is therefore the use of a co-crystal or a composition according to the invention as a biocide in industrial products, in particular as a preservative, antibacterial, fungicide or algaecide, especially in paints, coatings , fluids for metalworking, in the protection and preservation of wood, in personal care products or in cosmetic formulations.

Description of the figures

Figure 1: Graphic representation of the co-crystal of example 1.

Figure 2: IR spectrum of the co-crystal of example 1.

Figure 3: PXRD plot of the co-crystal of example 1.

Figure 4: DSC trace of the co-crystal of example 1.

Figure 5: Graphic representation of the co-crystal of example 2.

Figure 6: IR spectrum of the co-crystal of example 2.

Figure 7: PXRD plot of the co-crystal of example 2.

Figure 8: DSC trace of the co-crystal of example 2.

Figure 9: Graphic representation of the co-crystal of example 3.

Figure 10: IR API spectrum of the co-crystal of example 3.

Figure 11: PXRD plot of the co-crystal of example 3.

Figure 12: DSC trace of the co-crystal of example 3.

Figure 13: IR API of the co-crystal of example 4.

Figure 14: PXRD plot of the co-crystal of example 4.

Figure 15: DSC trace of the co-crystal of example 4.

Figure 16: Graphic representation of the co-crystal of example 5. Figure 17: IR API spectrum of the co-crystal of example 5.

Figure 18: PXRD plot of the co-crystal of example 5.

Figure 19: DSC trace of the co-crystal of example 5.

The invention is now illustrated by the following examples.

Examples

Materials and methods

The IR spectra were obtained by means of a Nicolet Nexus FTIR spectrophotometer equipped with the U-ATR device. Values have been reported as wave numbers à ̈ have been rounded to 1 cm <-1> after automatic assignment. Melting points were obtained by differential scanning calorimetry analysis (DSC, Mettler Toledo 823e).

X-ray diffraction of a single crystal

The data were collected at different temperatures with a Bruker KAPPA APEX II diffractometer with Mo-KÎ ± (Î »= 0.71073) radiation and a CCD detector. The Bruker KRYOFLEX device was used for low temperature acquisitions. The structures were solved and refined using the SIR2004 and SHELXL-97 programs, respectively. The refinement was performed using the least squares method on a complete matrix of F <2>. The hydrogen atoms were placed using standard geometric models and with their thermal parameters selected over those of their geminal atoms.

X-ray diffraction of powders

The X-ray diffraction experiments of the powders were performed with a Bruker D8 Advance diffractometer operating in reflection mode with Ge-monochromatic radiation Cu KÎ ± 1 (Î »= 1.5406 Ã…) and with a linear position-sensitive detector . The powder diffraction data were collected at room temperature with a 2Î range of 5-40 °, using 0.016 ° increments and an exposure time of 1.5 s per increment.

Example 1

Co-crystal containing 3-iodopropinyl butylcarbamate and 4- [2- (4-pyridinyl) ethyl] pyridine in 2: 1 molar ratio (1 co-crystal)

O I O I N ONONI

2 NH <+> NH N O O HN

This example demonstrates the ability of IPBC to co-crystallize with a neutral aromatic amine capable of acting as a halogen bond acceptor, such as 4- [2- (4-pyridinyl) ethyl] pyridine.

The rapid precipitation of the two compounds in an almost saturated acetonitrile solution results in the formation of a solid white powder having a melting point between 81 ° C and 83 ° C.

X-ray diffraction of a single crystal shows that in the IPBC co-crystal and 4- [2- (4-pyridinyl) ethyl] pyridine are present in a molar ratio of 2: 1, as shown in Figure 1. The reason basic structural in the co-crystal is a trimeric unit in which 4- [2- (4-pyridinyl) ethyl] pyridine acts as a bridge between two IPBC molecules through two I <â € ¦> N halogen bonds.

The dimensions and angles of the crystallographic unit cell are [a = 30.666 (3) b = 4.9869 (4) c = 21.068 (2)] and [Î ± = 90.00 β = 92.115 (6) γ = 90.00], respectively.

The IR spectrum of the co-crystal and its characteristic bands are shown in Figure 2.

Figure 3 shows the X-ray diffraction of powders (PXRD) of the co-crystal, whose main peaks in the range of values 2Î ̧ 5â40 ° are shown in table 1.

The DSC thermogram of co-crystal 1 is shown in Figure 4.

Table 1

Angle (2Î ̧) * d (Ã ...) Intensity%

2th = 5.117 ° 17.25577 2521 51.2

2th = 5.684 ° 15.53601 4923 100.0

2th = 8.644 ° 10.22081 1240 25.2

2th = 8.924 ° 9.90129 1792 36.4

2th = 9.274 ° 9.52842 907 18.4

2th = 11.445 ° 7.72521 3010 61.1

2th = 12.225 ° 7.23443 490 10.0

2th = 14.471 ° 6.11592 932 18.9

2th = 15.726 ° 5.63077 310 6.3

2th = 16.087 ° 5.50517 408 8.3

2th = 16.402 ° 5.40011 592 12.0

2th = 16.951 ° 5.22630 2000 40.6

2th = 17,228 ° 5.14312 872 17.7

2th = 17.997 ° 4.92493 576 11.7

2th = 18.382 ° 4.82269 644 13.1 th = 19.133 ° 4.63491 368 7.5 th = 19.692 ° 4.50459 476 9.7 th = 20.105 ° 4.41308 507 10.3 th = 21.176 ° 4.19213 350 7.1 th = 21.524 ° 4.12518 1449 29.4 th = 21.800 ° 4.07364 894 18.2 th = 22.221 ° 3.99734 4665 94.8 th = 22.663 ° 3.92047 2184 44.4 th = 23.181 ° 3.83400 1450 29.5 th = 24.580 ° 3.61886 373 7.6 th = 24.967 ° 3.56356 2850 57.9 th = 25.348 ° 3.51083 400 8.1 th = 25.876 ° 3.44043 339 6.9 th = 26.404 ° 3.37283 302 6.1 th = 27.191 ° 3.27701 783 15.9 th = 27.882 ° 3.19725 4091 83.1 th = 28.258 ° 3.15564 451 9.2 th = 28.838 ° 3.09341 1892 38.4 th = 29.185 ° 3.05747 373 7.6 th = 30.311 ° 2.94642 344 7.0 th = 30.988 ° 2.88354 260 5.3 th = 32.914 ° 2.71904 255 5.2 th = 33.516 ° 2.67 160 361 7.3 th = 34.345 ° 2.60901 250 5.1 th = 34.793 ° 2.57641 883 17.9 2th = 35.051 ° 2.55803 443 9.0

2th = 35.850 ° 2.50285 270 5.5

2th = 36.589 ° 2.45396 519 10.5

2th = 37.072 ° 2.42311 464 9.4

2th = 37.905 ° 2.37175 254 5.2

2th = 38.291 ° 2.34872 309 6.3

2th = 39.015 ° 2.30676 228 4.6

2th = 39.738 ° 2.26645 438 8.9

* Values ± 0.05 °

Compared to IPBC, the co-crystal thus obtained has a higher melting point, higher thermal stability, better workability and a higher degree of crystallinity. It is easy to handle in the operations required for the formation of tablets, for example in compression.

Example 2

Co-crystal containing 3-iodopropinyl butylcarbamate and 4,4â € ™ -bipyridine in molar ratio 2: 1 (2 co-crystal)

This example demonstrates the ability of IPBC to co-crystallize with another neutral aromatic amine capable of acting as a halogen bond acceptor, such as 4,4â € ™ -dipyridine.

In this case the formation of the co-crystal was obtained by slow precipitation from an ethanolic solution, which leads to the formation of a white powder.

The basic structural motif in the co-crystal is a trimeric unit, linked by halogen bonds, composed of a molecule of 4.4â € ™ -bipyridine and two molecules of IPBC, as shown in Figure 5.

The co-crystal is a crystalline solid product having a melting point between 112 ° C and 114 ° C. The dimensions and angles of the crystallographic unit cell are [a = 28.683 (2) b = 4.9270 (4) c = 21.429 (2)] and [Î ± = 90.00 β = 99.92 (2) γ = 90.00], respectively.

The IR spectrum of the co-crystal and its characteristic bands are shown in Figure 6.

Figure 7 shows the X-ray diffraction of powders (PXRD) of the co-crystal, whose main peaks in the range of values 2Î ̧ 5-40 ° are shown in Table 2.

The DSC thermogram of co-crystal 2 is shown in Figure 8.

Table 2

Angle (2Î ̧) * d (Ã ...) Intensity%

2th = 6.234 ° 14.16728 8558 100.0

2th = 8.358 ° 10.57069 353 4.1

2th = 9.560 ° 9.24440 679 7.9

2th = 12.160 ° 7.27286 269 3.1

2th = 12.521 ° 7.06371 1737 20.3

2th = 13.187 ° 6.70850 197 2.3

2th = 13.841 ° 6.39289 399 4.7

2th = 16.255 ° 5.44854 2148 25.1

2th = 16,825 ° 5.26536 663 7.7

2th = 18.651 ° 4.75371 507 5.9

2th = 18.861 ° 4.70134 1402 16.4

th = 19.248 ° 4.60750 1051 12.3 th = 19.892 ° 4.45974 187 2.2 th = 20.400 ° 4.34990 797 9.3 th = 21.931 ° 4.04952 5931 69.3 th = 22.695 ° 3.91488 453 5.3 th = 23.110 ° 3.84554 991 11.6 th = 23.835 ° 3.73028 1084 12.7 th = 24.461 ° 3.63616 319 3.7 th = 24.826 ° 3.58348 679 7.9 th = 25.194 ° 3.53200 3287 38.4 th = 26.333 ° 3.38179 452 5.3 th = 27.465 ° 3.24488 325 3.8 th = 27.980 ° 3.18637 877 10.2 th = 28.475 ° 3.13207 786 9.2 th = 28.928 ° 3.08399 349 4.1 th = 29.463 ° 3.02919 427 5.0 th = 29.735 ° 3.00209 298 3.5 th = 30.264 ° 2.95086 255 3.0 th = 30.571 ° 2.92189 319 3.7 th = 31.311 ° 2.85455 198 2.3 th = 32.653 ° 2.74021 176 2.1 th = 33.314 ° 2.68732 203 2.4 th = 33.439 ° 2.67760 232 2.7 th = 33.914 ° 2.64116 241 2.8 th = 34.205 ° 2.61934 475 5.6 2th = 34.762 ° 2.57862 234 2.7

2th = 36.146 ° 2.48303 206 2.4

2th = 37.672 ° 2.38589 384 4.5

2th = 38.213 ° 2.35331 596 7.0

2th = 38.614 ° 2.32980 258 3.0

* Values ± 0.05 °

Compared to IPBC, the co-crystal thus obtained has a higher melting point, higher thermal stability, better workability and a higher degree of crystallinity. It is easy to handle in the operations required for the formation of tablets, for example in compression.

Example 3

Co-crystal containing 3-iodopropinyl butylcarbamate and tetrabutylammonium iodide in 3: 1 molar ratio (3 co-crystal)

In this example the ability of IPBC to co-crystallize with a halide deriving from an organic salt such as tetrabutylammonium iodide is demonstrated.

The formation of the co-crystal was achieved by mechano-chemical synthesis using a ball mill, using a stoichiometric ratio of 1: 3 between tetrabutylammonium iodide and IPBC.

The co-crystal obtained contains one molecule of tetrabutylammonium iodide and three molecules of IPBC, as shown in the graphical representation of Figure 9.

The co-crystal is a crystalline solid product having a melting point between 42 ° C and 47.5 ° C. The dimensions and angles of the crystallographic unit cell are [a = 10.7688 (9) b = 20.204 (2) c = 23.735 (2)] and [Î ± = 90.00 β = 94.778 (2) γ = 90.00], respectively.

The IR spectrum of the co-crystal and its characteristic bands are shown in Figure 10.

Figure 11 shows the X-ray diffraction of powders (PXRD) of the co-crystal, whose main peaks in the range of values 2Î ̧ 5-40 ° are shown in Table 3.

The DSC thermogram of co-crystal 3 is shown in Figure 12.

Table 3

Angle (2Î ̧) * d (Ã ...) Intensity%

2th = 9.285 ° 9.51690 513 53.5

2th = 14.485 ° 6.11006 445 46.5

2th = 16.322 ° 5.42635 469 49.0

2th = 17,432 ° 5.08330 346 36.1

2th = 17.729 ° 4.99868 537 56.1

2th = 18.440 ° 4.80755 373 38.9

2th = 20.246 ° 4.38272 517 54.0

2th = 20.698 ° 4.28791 438 45.7

2th = 21.072 ° 4.21276 423 44.2

2th = 21.331 ° 4.16217 629 65.7

2th = 22.261 ° 3.99035 958 100.0

th = 22.903 ° 3.87977 590 61.6 th = 23.605 ° 3.76596 613 64.0 th = 23.968 ° 3.70974 484 50.5 th = 24.305 ° 3.65910 616 64.3 th = 25.009 ° 3.55775 580 60.5 th = 25.670 ° 3.46761 363 37.9 th = 26.129 ° 3.40770 406 42.4 th = 26.507 ° 3.35996 423 44.2 th = 26.730 ° 3.33240 343 35.8 th = 27.359 ° 3.25726 326 34.0 th = 27.893 ° 3.19608 432 45.1 th = 28.399 ° 3.14030 389 40.6 th = 28.918 ° 3.08502 372 38.8 th = 30.514 ° 2.92722 311 32.5 th = 31.221 ° 2.86256 302 31.5 th = 31.654 ° 2.82441 322 33.6 th = 32.085 ° 2.78741 349 36.4 th = 32.592 ° 2.74517 308 32.2 th = 33.490 ° 2.67360 323 33.7 th = 34.033 ° 2.63217 246 25.7 th = 34.608 ° 2.58975 249 26.0 th = 34.973 ° 2.56357 314 32.8 th = 35.533 ° 2.52440 269 28.1 th = 36.332 ° 2.47069 261 27.2 th = 36.772 ° 2.44214 278 29.0 2th = 37.328 ° 2.40703 225 23.5

2th = 38.414 ° 2.34144 277 28.9

* Values ± 0.1 °

Compared to IPBC, the co-crystal thus obtained has a lower melting point, a higher solubility and better workability in an aqueous medium. In particular, the aqueous solubility is about 40% higher than that of IPBC.

Example 4

Co-crystal containing 3-iodopropinyl butyl carbamate and calcium chloride in 4: 1 molar ratio (4 co-crystal)

OI <Cl-> I O 2 O I <+> CaCl2OHx O

O NH HN

4 NH

IPBC

This example demonstrates the ability of IPBC to co-crystallize with a halide deriving from an inorganic salt such as calcium chloride.

The formation of the co-crystal was achieved by mechano-chemical synthesis using a ball mill, using a stoichiometric ratio of 1: 4 between calcium chloride and IPBC.

The composition of the co-crystal was detected by analyzing the DSC trace, where the presence of the peaks of the starting products was not observed.

The co-crystal is a crystalline solid product with a melting point of 83-86 ° C.

The IR spectrum of the co-crystal and its characteristic bands are shown in Figure 13.

Figure 14 shows the X-ray diffraction of powders (PXRD), whose main peaks in the range of values 2Î ̧ 5âˆ40 ° are shown in Table 4.

The DSC thermogram of co-crystal 4 is shown in Figure 15.

Table 4

Angle (2Î ̧) d (Ã ...) Intensity%

2th = 6.581 ° 13.41984 5844 16.2

2th = 7.314 ° 12.07749 10715 29.7

2th = 8.160 ° 10.82602 4892 13.6

2th = 9.674 ° 9.13549 16217 45.0

2th = 11.059 ° 7.99382 7263 20.1

2th = 11.991 ° 7.37478 4418 12.3

2th = 13.299 ° 6.65245 6966 19.3

2th = 15.631 ° 5.66483 4674 13.0

2th = 15.982 ° 5.54118 6113 17.0

2th = 17.374 ° 5.10003 8718 24.2

2th = 18.517 ° 4.78765 9325 25.9

2th = 19.365 ° 4.57995 11180 31.0

2th = 20.091 ° 4.41616 3184 8.8

2th = 21.313 ° 4.16552 4102 11.4

2th = 22.282 ° 3.98664 36057 100.0

2th = 23.054 ° 3.85484 3660 10.2

2th = 23.469 ° 3.78751 3136 8.7

2th = 24.435 ° 3.63994 6628 18.4

2th = 24.990 ° 3.56041 12456 34.5

2th = 26.159 ° 3.40384 5054 14.0

2th = 26.775 ° 3.32689 4703 13.0

2th = 27.659 ° 3.22252 11372 31.5

2th = 28.514 ° 3.12789 5945 16.5

2th = 29.588 ° 3.01671 6588 18.3

2th = 30.368 ° 2.94095 2644 7.3

2th = 31.158 ° 2.86817 4800 13.3

2th = 31.838 ° 2.80850 8422 23.4

2th = 32.766 ° 2.73101 2388 6.6

2th = 33.979 ° 2.63621 4478 12.4

2th = 34.729 ° 2.58102 3049 8.5

2th = 35.337 ° 2.53800 2887 8.0

2th = 36.000 ° 2.49271 2816 7.8

2th = 36.603 ° 2.45308 2980 8.3

2th = 37.030 ° 2.42574 3009 8.3

2th = 37.436 ° 2.40037 3085 8.6

2th = 38.110 ° 2.35946 4670 13.0

2th = 38.968 ° 2.30947 3168 8.8

2th = 39.475 ° 2.28092 2995 8.3

* Values ± 0.05 °

Compared to IPBC, the co-crystal thus obtained has a higher melting point, a higher solubility and better workability in an aqueous medium. In particular, the aqueous solubility is approximately 50% higher than that of IPBC.

Example 5

Co-crystal containing 3-iodopropinyl butylcarbamate and N, Nâ € ™ -bis (4-pyridylcarbonyl) -1,6-hexanediamine in molar ratio 2: 1 (co-crystal 5)

O I

2 O

NH O H N I O

IPBC N N O

HN O I N H O

OR

NH

O H N N N N H O

In this example IPBC was co-crystallized with N, Nâ € ™ -bis (4-pyridylcarbonyl) -1,6-hexanediamine either by slow evaporation from alcoholic solutions or by mechanical-chemical synthesis in a ball mill, using a ratio of 1: 2 between the co-crystallization agent and IPBC.

In the co-crystal obtained there is a ratio of 1: 2 between the co-crystallization agent and IPBC, as shown in the graphical representation of Figure 16.

The co-crystal is a crystalline solid product with a melting point of 132 ° C. The dimensions and angles of the crystallographic unit cell are [a = 29.4501 (18) b = 5.1100 (3) c = 27.9417 (17)] and [Î ± = 90.00 β = 118.566 (3) γ = 90.00], respectively.

The IR spectrum of the co-crystal and its characteristic bands are shown in Figure 17.

Figure 18 shows the X-ray diffraction of powders (PXRD) of the co-crystal, whose main peaks in the range of values 2Î ̧ 5-40 ° are shown in Table 5.

The DSC thermogram of co-crystal 5 is shown in Figure 19.

Table 5

Angle (2Î ̧) d (Ã…) Intensity% 2th = 5.887 ° 14.99966 1231 18.2 2th = 6.951 ° 12.70619 545 8.1 2th = 10.380 ° 8.51551 690 10.2 2th = 11.831 ° 7.47444 3530 52.3 2th = 13.013 ° 6.79759 324 4.8 2th = 13.477 ° 6.56468 591 8.8 2th = 13.961 ° 6.33814 1111 16.5 2th = 14.270 ° 6.20161 272 4.0 2th = 15.441 ° 5.73399 1653 24.5 2th = 16.713 ° 5.30018 510 7.6 2th = 17.132 ° 5.17156 244 3.6 2th = 17.945 ° 4.93909 411 6.1 2th = 18.816 ° 4.71240 331 4.9 2th = 19.095 ° 4.64417 378 5.6 2th = 19.516 ° 4.54479 300 4.4 2th = 20.075 ° 4.41964 366 5.4 2th = 20.950 ° 4.23697 1050 15.6 2th = 21.366 ° 4.15541 563 8.3 2th = 21.916 ° 4.05229 740 11.0 2th = 22.784 ° 3.89988 6751 100.0 2th = 23.513 ° 3.78060 855 12.7 2th = 23.856 ° 3.72703 939 13.9 2th = 24.326 ° 3.65609 332 4.9 2th = 25.096 ° 3.54550 509 7.5

2th = 25.760 ° 3.45568 376 5.6

2th = 26.944 ° 3.30641 653 9.7

2th = 27.924 ° 3.19254 305 4.5

2th = 28.684 ° 3.10973 548 8.1

2th = 29.094 ° 3.06678 276 4.1

2th = 29.709 ° 3.00471 330 4.9

2th = 30.531 ° 2.92568 430 6.4

2th = 31.214 ° 2.86315 419 6.2

2th = 31.568 ° 2.83188 367 5.4

2th = 32.461 ° 2.75600 241 3.6

2th = 32.802 ° 2.72810 284 4.2

2th = 34.124 ° 2.62537 365 5.4

2th = 34.688 ° 2.58393 478 7.1

2th = 36.154 ° 2.48246 505 7.5

2th = 36.966 ° 2.42976 398 5.9

2th = 37.750 ° 2.38110 561 8.3

2th = 39.102 ° 2.30185 457 6.8

* Values ± 0.05 °

Compared to IPBC, the co-crystal thus obtained has a higher melting point, higher thermal stability, better workability and a higher degree of crystallinity. It is easily handled in the operations required for the formation of tablets, for example in compression.

Claims (14)

CLAIMS 1. A co-crystal of the compound 3-iodopropinyl butylcarbamate with a co-crystallization agent selected from the group of aromatic heterocycles containing at least one basic nitrogen atom, aliphatic amines, halides deriving from organic or inorganic salts, phosphates, carboxylates, in which said agent is in the liquid or solid state at room temperature and is bound to said compound through at least one halogen bond. 2. A co-crystal according to claim 1 wherein the aromatic heterocycles containing at least one nitrogen atom of basic nature are selected from derivatives of pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, thiazole, isothiazole, oxazole, isoxazole and their benzocondensated derivatives . 3. A co-crystal according to claim 2 wherein the pyridine derivatives have the general formula (I) <N> L N (THE) where L is chosen from - (CH2) n-, where n is 0 or an integer from 1 to 6, and -C (O) -NH- (CH2) m-NH-C (O) -, in which m is an integer from 2 to 6, and in which one or both of the pyridine rings can be benzocondensed. 4. A co-crystal according to claim 3 wherein the pyridine derivatives are 4,4â € ™ -bipyridyl, 4- [2- (4-pyridinyl) ethyl] pyridine, or N, Nâ € ™ -bis (4- pyridylcarbonyl) -1,6-hexanediamine. 5. A co-crystal according to claim 1, in which the aliphatic amines are selected in the group of formula R <1> R <2> R <3> N in which R <1>, R <2> and R <3 > C1-C6alkyl, C3-C7cycloalkyl are independently selected from the hydrogen group; or R <1> is as defined above and R <2> and R <3>, taken together with the nitrogen atom to which they are bonded, form a 4-7-membered heterocyclic nitrogen ring optionally containing an oxygen atom or sulfur or a further nitrogen atom, said further nitrogen atom being replaced by a group R <1> as defined above. 6. A co-crystal according to claim 1, in which the organic halides are tetraalkylammonium halides of formula R4N <+> X <-> in which each each R can be independently a C1-C6 alkyl and X <-> is a halide. 7. A co-crystal according to claim 6 wherein the organic halide is tetrabutylammonium iodide. 8. A co-crystal according to claim 1 wherein the inorganic halide is the halide of an alkali metal, alkaline earth or of a transition metal selected from iron and zinc, or a tin halide. 9. A co-crystal according to claim 8, wherein the inorganic halide is calcium chloride. 10. A co-crystal according to claim 4 selected from the following group: - co-crystal containing 3-iodopropinyl butylcarbamate and 4- [2- (4-pyridinyl) ethyl] pyridine in a 2: 1 molar ratio - co-crystal containing 3-iodopropinyl butylcarbamate and 4,4â € ™ -bipyridine in a molar ratio of 2: 1; - co-crystal containing 3-iodopropinyl butylcarbamate and tetrabutylammonium iodide in a molar ratio of 3: 1; - co-crystal containing 3-iodopropinyl butylcarbamate and calcium chloride in a 4: 1 molar ratio; - co-crystal containing 3-iodopropinyl butylcarbamate and N, Nâ € ™ -bis (4-pyridylcarbonyl) -1,6-hexanediamine in a 2: 1 molar ratio. 11. Composition containing a co-crystal of claims 1-10, a solvent or diluent and optionally additives and / or a biocidal active agent. 12. Use of a co-crystal according to claims 1-10 or a composition according to claim 11 as a biocide in industrial products, in particular as a preservative, antibacterial, fungicide or algaecide, especially in paints, coatings, fluids for the processing of metals, in the protection and preservation of wood, in personal care products or in cosmetic formulations. 13. Industrial products containing a co-crystal as defined in claim 1. 14. Process for the preparation of a co-crystal as defined in claim 1, comprising the steps of: a) contacting 3-iodopropinyl butylcarbamate with a co-crystallization agent capable of forming at least one halogen bond with said 3-iodopropinyl butylcarbamate, in conditions of crystallization such as to form a solid phase in which the 3-iodopropinyl butylcarbamate is said agent are linked together by at least one halogen bond; b) optional isolation of the co-crystals formed in step a).